Mortality burden of pre-treatment weight loss in patients with non-small-cell lung cancer: A systematic literature review and meta-analysis.

Cachexia, with weight loss (WL) as a major component, is highly prevalent in patients with cancer and indicates a poor prognosis. The primary objective of this study was to conduct a meta-analysis to estimate the risk of mortality associated with cachexia (using established WL criteria prior to treatment initiation) in patients with non-small-cell lung cancer (NSCLC) in studies identified through a systematic literature review. The review was conducted according to PRISMA guidelines. Embase® and PubMed were searched to identify articles on survival outcomes in adult patients with NSCLC (any stage) and cachexia published in English between 1 January 2016 and 10 October 2021. Two independent reviewers screened titles, abstracts and full texts of identified records against predefined inclusion/exclusion criteria. Following a feasibility assessment, a meta-analysis evaluating the impact of cachexia, defined per the international consensus criteria (ICC), or of pre-treatment WL ≥ 5% without a specified time interval, on overall survival in patients with NSCLC was conducted using a random-effects model that included the identified studies as the base case. The impact of heterogeneity was evaluated through sensitivity and subgroup analyses. The standard measures of statistical heterogeneity were calculated. Of the 40 NSCLC publications identified in the review, 20 studies that used the ICC for cachexia or reported WL ≥ 5% and that performed multivariate analyses with hazard ratios (HRs) or Kaplan-Meier curves were included in the feasibility assessment. Of these, 16 studies (80%; n = 6225 patients; published 2016-2021) met the criteria for inclusion in the meta-analysis: 11 studies (69%) used the ICC and 5 studies (31%) used WL ≥ 5%. Combined criteria (ICC plus WL ≥ 5%) were associated with an 82% higher mortality risk versus no cachexia or WL < 5% (pooled HR [95% confidence interval, CI]: 1.82 [1.47, 2.25]). Although statistical heterogeneity was high (I2 = 88%), individual study HRs were directionally aligned with the pooled estimate, and there was considerable overlap in CIs across included studies. A subgroup analysis of studies using the ICC (HR [95% CI]: 2.26 [1.80, 2.83]) or WL ≥ 5% (HR [95% CI]: 1.28 [1.12, 1.46]) showed consistent findings. Assessments of methodological, clinical and statistical heterogeneity indicated that the meta-analysis was robust. Overall, this analysis found that ICC-defined cachexia or WL ≥ 5% was associated with inferior survival in patients with NSCLC. Routine assessment of both weight and weight changes in the oncology clinic may help identify patients with NSCLC at risk for worse survival, better inform clinical decision-making and assess eligibility for cachexia clinical trials.

Prognostic risk factors for moderate-to-severe exacerbations in patients with chronic obstructive pulmonary disease: a systematic literature review.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. COPD exacerbations are associated with a worsening of lung function, increased disease burden, and mortality, and, therefore, preventing their occurrence is an important goal of COPD management. This review was conducted to identify the evidence base regarding risk factors and predictors of moderate-to-severe exacerbations in patients with COPD. METHODS: A literature review was performed in Embase, MEDLINE, MEDLINE In-Process, and the Cochrane Central Register of Controlled Trials (CENTRAL). Searches were conducted from January 2015 to July 2019. Eligible publications were peer-reviewed journal articles, published in English, that reported risk factors or predictors for the occurrence of moderate-to-severe exacerbations in adults age ≥ 40 years with a diagnosis of COPD. RESULTS: The literature review identified 5112 references, of which 113 publications (reporting results for 76 studies) met the eligibility criteria and were included in the review. Among the 76 studies included, 61 were observational and 15 were randomized controlled clinical trials. Exacerbation history was the strongest predictor of future exacerbations, with 34 studies reporting a significant association between history of exacerbations and risk of future moderate or severe exacerbations. Other significant risk factors identified in multiple studies included disease severity or bronchodilator reversibility (39 studies), comorbidities (34 studies), higher symptom burden (17 studies), and higher blood eosinophil count (16 studies). CONCLUSIONS: This systematic literature review identified several demographic and clinical characteristics that predict the future risk of COPD exacerbations. Prior exacerbation history was confirmed as the most important predictor of future exacerbations. These prognostic factors may help clinicians identify patients at high risk of exacerbations, which are a major driver of the global burden of COPD, including morbidity and mortality.

Relative efficacy of varicella vaccines: network meta-analysis of randomized controlled trials.

OBJECTIVE: Although varicella vaccination is highly effective, no head-to-head randomized controlled trials (RCTs) have compared the efficacy of different vaccine formulations. This study assessed the relative efficacy of different varicella vaccines using network meta-analysis (NMA). METHODS: We estimated the relative efficacies of varicella vaccines and dosing regimens from RCTs using Bayesian NMA. Modeling-based time-series NMA (MBNMA) was performed, accounting for differences in time since vaccination, to extrapolate long-term vaccine efficacy (VE). RESULTS: Eight RCTs were included based on systematic review of biomedical databases. Efficacy data were reported for four varicella-containing vaccines: Varivax (V-MSD, one and two dose), Varilrix (V-GSK, one dose), Priorix-Tetra (MMRV-GSK, one dose), and Sinovac (V-Sinovac, one dose). All varicella vaccines were effective versus no vaccination. Two-dose V-MSD (98.29%, 95% credible interval [CrI] 96.08-99.23) showed significantly higher VE versus all one-dose varicella-containing vaccines, but no significant difference versus two-dose MMRV-GSK (95.19%, 95% CrI 90.3-97.63). Two-dose MMRV-GSK showed higher VE than one-dose V-GSK (66.47%; 95% CrI 43.02-79.43), but no significant differences in VE versus one-dose V-MSD or one-dose V-Sinovac. In one-dose comparisons, V-MSD showed significantly higher VE (93.09%, 95% CrI 89.13-95.96) than V-GSK, but no significant difference versus V-Sinovac (89.22%; 95% CrI 67.1-96.5). MBNMA indicated that protection against varicella was sustained without waning over the 10 year follow-up. CONCLUSIONS: Our study reported higher VE for two-dose V-MSD and MMRV-GSK. Among one-dose formulations, one-dose V-MSD was more efficacious than one-dose V-GSK. Policymakers should take into consideration differences in VE when implementing one- versus two-dose strategies in universal vaccination programs.

A Systematic Literature Review of the Humanistic Burden of COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide, causing substantial economic and social burden. OBJECTIVE: This review assessed the patient-reported humanistic burden associated with moderate to very severe COPD, specifically the impact on health-related quality of life (HRQoL), symptoms, limitations in daily life, and emotional implications, through the use of HRQoL instruments. METHODS: A systematic review was conducted to retrieve relevant clinical data from published literature using a representative sample of countries where healthcare systems provide wide availability of COPD medications and/or universal coverage includes respiratory medicines (Australia, Canada, China, France, Germany, Italy, Spain, the UK, and the USA). The primary inclusion criteria were patients with moderate to very severe COPD. HRQoL was quantified with non-disease-specific and disease-specific questionnaires. RESULTS: In total, 82 studies from 95 publications presented HRQoL data from patients with moderate to very severe COPD. Patient-reported HRQoL declined with worsening airflow limitation, advancing GOLD group, and increasing exacerbation frequency. Both increasing frequency of hospitalization for COPD exacerbations and recurrent hospitalization adversely impacted HRQoL. Comorbidity incidence was higher in patients with increased airflow limitation. It was associated with a further decline in HRQoL and increased depression and anxiety, particularly as disease-associated pain worsened. Physical activity improved HRQoL over time. CONCLUSION: This review highlighted the impact of exacerbations and associated hospitalizations on the humanistic burden of COPD. These findings underline the importance of managing COPD actively, including prompt and appropriate use of pharmacological and non-pharmacological therapies that can improve symptoms and reduce the risk of exacerbations, thereby lessening the humanistic burden. Future reviews could consider a broader range of countries and publications to further assess the humanistic impact of COPD in low- and middle-income economies.

Efficacy and Safety of Budesonide/Glycopyrronium/Formoterol Fumarate versus Other Triple Combinations in COPD: A Systematic Literature Review and Network Meta-analysis.

In patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations or symptoms, despite being prescribed dual long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) or inhaled corticosteroid (ICS)/LABA therapies, triple ICS/LAMA/LABA therapy is recommended. A previous network meta-analysis showed comparable efficacy of the ICS/LAMA/LABA, budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR) 320/18/9.6 µg, to other fixed-dose and open combination triple therapies at 24 weeks in COPD. Subsequently, the ETHOS study was published, including data for 8509 patients, assessing the efficacy and safety of BUD/GLY/FOR over 52 weeks. This network meta-analysis (NMA) was conducted to compare the relative efficacy, safety, and tolerability of BUD/GLY/FOR 320/18/9.6 µg with other fixed-dose and open combination triple therapies in COPD over 52 weeks, including data from ETHOS. A systematic literature review was conducted to identify ≥ 10-week randomized controlled trials, including ≥ 1 fixed-dose or open combination triple-therapy arm, in patients with moderate-to-very severe COPD. The methodologic quality and risk of bias of included studies were assessed. Study results were combined using a three-level hierarchical Bayesian NMA model to assess efficacy and safety outcomes at or over 24 and 52 weeks. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies. Nineteen studies (n = 37,741 patients) met the inclusion criteria of the review; 15 contributed to the base case network. LAMA/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes for exacerbations, lung function, symptoms, health-related quality of life, safety, and tolerability, the efficacy and safety of BUD/GLY/FOR were comparable to those of other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium bromide/formoterol fumarate) and open combinations at or over 24 and 52 weeks. Sensitivity analyses and meta-regression results for exacerbation outcomes were broadly in line with the base case NMA. In this NMA, BUD/GLY/FOR 320/18/9.6 µg showed comparable efficacy versus other ICS/LAMA/LABA fixed-dose or open combination therapies in terms of reducing exacerbation rates and improving lung function, symptoms and health-related quality of life in patients with moderate-to-very-severe COPD, in line with previously published meta-analysis results of triple combinations in COPD. The safety and tolerability profile of BUD/GLY/FOR was also found to be comparable to other triple combination therapies.

Peptide receptor radiotherapy re-treatment in patients with progressive neuroendocrine tumors: A systematic review and meta-analysis.

BACKGROUND: This review and meta-analysis examined published evidence of peptide receptor radionuclide therapy (PRRT) re-treatment efficacy and safety in patients with advanced neuroendocrine tumors (NETs). METHODS: Embase, MEDLINE, MEDLINE In-Progress, and Cochrane CENTRAL were searched (database inception-present) to identify evidence of efficacy and safety of PRRT re-treatment in adults with NETs previously treated with 177Lu- and/or 90Y-PRRT. Progression-free survival (PFS), overall survival (OS), disease control rate (DCR) from time of re-treatment were assessed. Data were pooled using medians and variance for time-to-event outcomes and inverse-variance weighted proportions (Freeman-Tukey method) for binary outcomes. RESULTS: Of 567 studies screened, 13 reported re-treatment efficacy outcomes. In random-effects meta-analyses of 177Lu-PRRT re-treatment, median PFS (N = 7 studies [414patients]) was 12.52 months (95% CI 9.82-15.22) with moderate heterogeneity across studies (I2 = 50.5%), median OS (N = 2 [194 patients]) was 26.78 months (95% CI 18.73-34.83) with moderate-to-high heterogeneity (I2 = 57.5%), and DCR (N = 8 [347 patients]) was 71% (95% CI 66-75) with high heterogeneity (I2 = 81.5%). PFS was similar with either 177Lu-PRRT re-treatment alone or in combination with 90Y-PRRT. Grade 3/4 adverse events occurred in 5% (95% CI 2-8) of patients receiving 177Lu-PRRT re-treatment (N = 5 [271 patients]) with few grade 3/4 renal toxicities (0% [95% CI 0-1]). Pooled myelodysplastic syndrome and acute myeloid leukemia incidence was 0% (95%CI 0-2). CONCLUSION: Re-treatment with 177Lu-PRRT provided encouraging median PFS in patients with NETs with a safety profile similar to initial PRRT.

Efficacy of Budesonide/Glycopyrronium/Formoterol Fumarate Metered Dose Inhaler (BGF MDI) Versus Other Inhaled Corticosteroid/Long-Acting Muscarinic Antagonist/Long-Acting ß2-Agonist (ICS/LAMA/LABA) Triple Combinations in COPD: A Systematic Literature Review and Network Meta-analysis.

INTRODUCTION: Triple inhaled corticosteroid/long-acting muscarinic antagonist/long-acting ß2-agonist (ICS/LAMA/LABA) combination therapy is recommended for patients with chronic obstructive pulmonary disease (COPD) who experience further exacerbations/symptoms on dual LAMA/LABA or ICS/LABA therapy. The relative efficacy of budesonide/glycopyrronium/formoterol fumarate metered dose inhaler 320/18/9.6 µg (BGF MDI) in COPD was compared with other ICS/LAMA/LABA fixed-dose and open combination therapies in a network meta-analysis (NMA). METHODS: A systematic literature review was conducted to identify randomized controlled trials of at least 10-week duration, including at least one fixed-dose or open combination triple therapy arm, in patients with moderate to very severe COPD. Studies were assessed for methodological quality and risk of bias. A three-level hierarchical Bayesian NMA model was used to determine the exacerbation rate per patient per year as well as the following outcomes at week 24: changes from baseline in pre-dose trough forced expiratory volume in 1 s (FEV1), post-dose peak FEV1, and St. George's Respiratory Questionnaire (SGRQ) total score; proportion of SGRQ responders; and Transition Dyspnea Index focal score. Change from baseline in rescue medication use over weeks 12-24 was also analyzed. Meta-regression and sensitivity analyses were used to assess heterogeneity across studies. RESULTS: Eighteen studies (n = 29,232 patients) contributed to the NMA. ICS/LABA dual combinations were combined as a single treatment group to create a connected network. Across all outcomes, there were no statistically significant differences between BGF MDI and other triple ICS/LAMA/LABA fixed-dose (fluticasone furoate/umeclidinium/vilanterol and beclomethasone dipropionate/glycopyrronium/formoterol fumarate) and open combinations with data available within the network. Results from sensitivity analyses and meta-regression were consistent with the base-case scenario. CONCLUSION: This NMA suggested that BGF MDI has comparable efficacy to other ICS/LAMA/LABA fixed-dose and open triple combination therapies in reducing exacerbations and improving lung function and symptoms in patients with moderate to very severe COPD. Further research is warranted as additional evidence regarding triple therapies, especially fixed-dose combinations, becomes available.

Use of rituximab in adults with relapsing-remitting multiple sclerosis: a systematic literature review.

Objective: Rituximab is used as an off-label treatment for relapsing-remitting multiple sclerosis (RRMS); however, the comparative efficacy and safety of rituximab versus currently licensed disease-modifying drugs (DMDs) for RRMS is unknown. A systematic literature review was conducted to evaluate the available data pertaining to efficacy and safety of rituximab in adult patients with RRMS and highly active relapsing multiple sclerosis (HA-RMS); data quality was critically assessed via risk of bias (RoB) assessment.Methods: Biomedical literature databases were searched until mid-2018 and key proceedings were searched from 2016 to 2018. Critical appraisal of non-randomized studies was conducted using the Cochrane RoB assessment tool; randomized controlled trials (RCTs) were appraised using comprehensive assessment criteria based on the NICE guidelines.Results: Thirty-eight unique studies based on 49 publications were identified: 25 RRMS studies (one RCT) and 13 HA-RMS studies (no RCTs). The evidence among patients with RRMS generally favored rituximab in comparison to placebo (relapse rate) and interferons/glatiramer acetate (relapse rate and disability progression), although much of the non-randomized data were descriptive and/or not statistically significant. In comparison to placebo, rituximab was associated with a greater risk of adverse events. Two-thirds of the non-randomized RRMS studies were associated with critical/serious RoB; the single RCT was associated with low RoB. Furthermore, all of the non-randomized HA-RMS studies were associated with critical/serious RoB.Conclusions: Available evidence of off-label rituximab use for the treatment of patients with RRMS suggests generally favorable efficacy versus placebo and interferons/glatiramer acetate; however, the poor quality of the included studies limits any robust conclusions.

Matching-adjusted comparison of oral corticosteroid reduction in asthma: Systematic review of biologics.

BACKGROUND: Oral corticosteroid (OCS) treatment for severe asthma is associated with substantial disease burden. Thus, OCS dosage reduction is desirable. Relative efficacy of biologics in reducing OCS treatment for severe, uncontrolled asthma is not fully characterized. OBJECTIVE: We performed a matching-adjusted indirect comparison (MAIC) to assess the relative effects on OCS treatment reduction of three biologic asthma treatments. METHODS: In MAIC of benralizumab vs. mepolizumab and vs. dupilumab, patient-level data from the Phase III benralizumab OCS-sparing trial, ZONDA, were weighted to match treatment effect-modifying patient characteristics in comparator trials. RESULTS: After matching adjustment, mean difference between benralizumab and mepolizumab for OCS reduction was 6.08% (95% CI -22.22-34.38; P = .67) by week 24, and odds ratio of OCS elimination was 2.32 (95% CI 0.48-11.15; P = .29). A trend in annual asthma exacerbation rate reduction favouring benralizumab over mepolizumab was observed, although it was not statistically significant (rate ratio [RR] = 0.56 [95% CI 0.28-1.13; P = .11]). Mean difference between benralizumab and dupilumab for OCS reduction was -0.71% (95% CI -20.56-19.15; P = .94), and odds ratio of OCS elimination was 2.26 (95% CI 0.52-9.84; P = .28). A non-significant trend in annual asthma exacerbation rate reduction favouring benralizumab over dupilumab was observed (RR = 0.50 [95% CI 0.20-1.28; P = .15]). Effective sample size was 49% (72 vs. 148) and 25% (36 vs. 142) of original sample size for MAIC of benralizumab vs. mepolizumab and benralizumab vs. dupilumab, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Following patient baseline characteristics matching across clinical trials, benralizumab demonstrated efficacy comparable to mepolizumab and dupilumab for OCS dosage reduction, OCS elimination, and annual exacerbation rate reduction. Comparatively low effective sample sizes indicated substantial differences for patient populations between ZONDA and mepolizumab and dupilumab trials.

Systematic review and network meta-analysis of the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler in comparison with other long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combinations in COPD.

BACKGROUND: Dual bronchodilation with a long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) fixed-dose combination (FDC) is an established treatment strategy for chronic obstructive pulmonary disease (COPD). The relative efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI 18/9.6 µg) in patients with moderate-to-very severe COPD, compared with other licensed LAMA/LABA FDCs, was investigated using an integrated Bayesian network meta-analysis (NMA). METHODS: A systematic literature review and subsequent screening process identified randomized controlled trials of ⩾10 weeks' duration that enrolled patients aged ⩾40 years with moderate-to-very severe COPD and included at least one LAMA/LABA FDC or open LAMA + LABA treatment arm. NMAs were conducted for outcomes including change from baseline in forced expiratory volume in 1 s (FEV1), St George's Respiratory Questionnaire (SGRQ), and transition dyspnea index (TDI) parameters, annualized rate of exacerbations, use of rescue medication, adverse events, and all-cause withdrawals. Meta-regression and sensitivity analyses accounted for heterogeneity across studies. RESULTS: In total, 29 studies including 34,617 patients contributed to the NMA for efficacy or safety outcomes at week 24 or exacerbations. For all LAMA/LABA FDCs with data available, significantly greater improvements in FEV1 [trough, peak, and area under the curve (AUC)0-4], SGRQ total score and TDI focal score at week 24, and annualized rate of moderate-to-severe exacerbations, were observed versus placebo. Where indirect comparisons were possible, differences between GFF MDI and other LAMA/LABA FDCs were small relative to established margins of clinical relevance, and not statistically significant. The safety and tolerability profile of GFF MDI was consistent with other LAMA/LABA FDCs and placebo. The results of the meta-regression were generally similar to the base case. CONCLUSIONS: GFF MDI demonstrated comparable efficacy and safety outcomes to other LAMA/LABA FDCs. Personalization of treatment choice within the class on the basis of other factors such as patient preference may be appropriate.

Estimating the comparative efficacy of cladribine tablets versus alternative disease modifying treatments in active relapsing-remitting multiple sclerosis: adjusting for patient characteristics using meta-regression and matching-adjusted indirect treatment comparison approaches.

Objectives: To estimate the comparative efficacy of cladribine tablets versus alternative disease modifying therapies (DMTs) - fingolimod, natalizumab, alemtuzumab and ocrelizumab - in adults with active relapsing-remitting multiple sclerosis (RRMS), using meta-regression to provide subpopulation-specific estimates of drug effect. Additionally, to determine the feasibility of conducting a matching-adjusted indirect comparison (MAIC) to validate the meta-regression results. Methods: A published systematic literature review (SLR) identified studies evaluating the efficacy of cladribine tablets and alternative DMTs in the management of active RRMS. A series of meta-regression models were run with adjustment for baseline risk, fitted to data from the intention-to-treat cohorts of trials identified in the SLR. A non-parametric MAIC analysis adjusted for differences between studies by reweighting patient-level data from the index trial to match the mean baseline characteristics reported for trials with only aggregate data. Results: The meta-regression analysis showed significant overlap in credible intervals for the hazard ratios of 6 month confirmed disability progression (CDP-6M) and annualized relapse rate (ARR), with no therapy statistically dominating in terms of efficacy and all therapies estimated to reduce the ARR compared to placebo in all subpopulations. In the MAIC analysis, cladribine tablets showed a reduction in CDP-6M and ARR comparable to alemtuzumab before and after matching. Conclusion: This analysis has demonstrated that cladribine tablets have comparable relative efficacy to other highly efficacious DMTs in active RRMS across all subpopulations, thus validating the comparative effectiveness results from previous network meta-analysis. The MAIC analysis showed that cladribine tablets are comparable in efficacy to alemtuzumab in the treatment of patients with RRMS.

Matching-adjusted indirect comparison of benralizumab versus interleukin-5 inhibitors for the treatment of severe asthma: a systematic review.

Benralizumab is an interleukin-5 receptor α-directed cytolytic monoclonal antibody that directly depletes eosinophils. Its relative efficacy versus other IL-5-targeted treatments for patients with severe, uncontrolled asthma is not yet fully characterised.We performed a matching-adjusted indirect comparison (MAIC) of benralizumab versus mepolizumab and reslizumab. Trials were selected through systematic review and evaluation of trial methods. Benralizumab patient-level data were weighted to match treatment-effect-modifying patient characteristics of comparator trials before indirect efficacy comparisons.After matching adjustment, benralizumab and mepolizumab reduced exacerbations versus placebo by 52% and 49%, respectively (rate ratio [RR] 0.94, 95% CI 0.78-1.13; n=1524) and reduced the rate of exacerbations requiring hospitalisation/emergency department visit by 52% and 52%, respectively (RR 1.00, 95% CI 0.57-1.75; n=1524). Benralizumab and mepolizumab similarly improved pre-bronchodilator forced expiratory volume in 1 s at 32 weeks (difference 0.03 L, 95% CI -0.06-0.12; n=1443). Benralizumab and reslizumab patient populations were too dissimilar to generate a sufficient effective sample size to produce a reliable estimate for MAIC.MAIC is a robust way to indirectly compare treatment efficacies from trials with heterogeneous patient populations. When baseline patient characteristics were matched across asthma trials, benralizumab and mepolizumab yielded similar efficacy.

Management of trauma pain in the emergency setting: low-dose methoxyflurane or nitrous oxide? A systematic review and indirect treatment comparison.

BACKGROUND: Low-dose methoxyflurane and nitrous oxide (N2O; 50:50 with oxygen) are both self-administered, self-titrated, rapid-acting, nonnarcotic, and noninvasive inhalational agents with similar onset times of pain relief. The aim of this review was to compare the clinical efficacy, safety, and tolerability of these analgesics in emergency care. MATERIALS AND METHODS: A systematic literature search and review according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were performed using Embase, Medline, the Cochrane Library, several clinical trial registers, and emergency-medicine conference material. RESULTS: Although both compounds have been used for many years in emergency care, the search found only a few controlled studies and no head-to-head trials performed in this setting. Two double-blind, randomized studies comparing their respective study medication (low-dose methoxyflurane or N2O) to placebo were identified that could be compared in an indirect approach by using placebo as a bridging comparator. Both agents provided rapid pain relief to trauma patients, with no significant differences between them; both treatments were generally well tolerated. CONCLUSION: Both low-dose methoxyflurane and N2O are suitable options for the pain treatment of trauma patients in the emergency setting. Due to the ease of administration and portability, inhaled low-dose methoxyflurane, however, may not only offer advantages in emergency situations in remote or difficult-to-reach locations and mass-casualty situations but also be of significant value in urban and rural environments.

Systematic literature review and network meta-analysis of cladribine tablets versus alternative disease-modifying treatments for relapsing-remitting multiple sclerosis.

OBJECTIVE: To assess the comparative efficacy and safety of cladribine tablets versus alternative disease modifying treatments (DMTs) in patients with active relapsing-remitting multiple sclerosis (RRMS), and in a subgroup with high disease activity (HRA + DAT), using systematic literature review (SLR) and network meta-analysis (NMA). METHODS: MEDLINE, Embase, MEDLINE In-Process and CENTRAL databases were systematically searched to identify English-language publications of relevant studies of approved DMTs for RRMS. Searches were conducted from database inception to January 2017. Conference websites and trial registries were also searched. NMA considered the effects of DMTs on annualized relapse rate (ARR), confirmed disease progression (CDP), no evidence of disease activity (NEDA) and safety. RESULTS: Of 10,825 articles retrieved and screened, 44 studies assessing 12 DMTs contributed to the NMA. In patients with active RRMS, cladribine tablets were associated with a significant 58% reduction in ARR versus placebo (p < .05); cladribine tablets were similar or significantly better than other DMT regimens and ranked fourth among DMTs, behind alemtuzumab, natalizumab and ocrelizumab. For CDP for 6 months and NEDA, improvements with cladribine tablets were significantly greater than those of placebo (p < .05), with no comparator DMT demonstrating significantly better results. Similar findings were reported in the HRA + DAT population. Overall adverse event risk for cladribine tablets did not differ significantly from that of placebo and most alternative DMTs. CONCLUSION: In this first NMA to consider cladribine tablets, ocrelizumab and daclizumab for treatment of RRMS, cladribine tablets are a comparatively effective and safe alternative to other DMTs in both active RRMS and HRA + DAT populations.

PD-L1 expression in advanced NSCLC: Insights into risk stratification and treatment selection from a systematic literature review.

Tumors can evade immune detection by exploiting inhibitory immune checkpoints such as the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) pathway. Antibodies that block this pathway offer a promising new approach to treatment in advanced/metastatic non-small cell lung cancer (NSCLC). A systematic review of the literature was conducted to assess the association of PD-L1 with important patient and disease characteristics, the prognostic significance of PD-L1 expressing NSCLC tumors, and the value of PD-L1 as a predictive biomarker of response to anti-PD-1/PD-L1 treatments in advanced/metastatic NSCLC. A total of 35 eligible studies were selected for analysis. Methods used to determine PD-L1 in NSCLC tissue varied considerably; with different PD-L1 antibodies, antibody detection methods, and staining cut-offs. Immunohistochemistry was the most frequent type of PD-L1 assay. Overall, study evidence did not support an association between PD-L1 expression and gender, age, smoking history, tumor histology (adenocarcinoma vs. squamous cell carcinoma), performance status, pathologic tumor grade or EGFR/KRAS/ALK mutational status. In several studies, high PD-L1 expression was associated with shorter survival compared with low expression. Most evidence indicated that patients with high vs. low PD-L1 expression were more likely to experience treatment benefit with anti-PD-1/PD-L1 agents (nivolumab, pembrolizumab, durvalumab, atezolizumab, and avelumab) in advanced NSCLC. Variability in the methods used to determine PD-L1 expression in NSCLC tissue suggests a need for standardized use of well-validated PD-L1 diagnostic assays. Although considerable research links PD-L1 expression in tumors to shorter survival in advanced/metastatic NSCLC, its use as a prognostic factor requires more study. As studies of anti-PD-1/PD-L1 agents continue, PD-L1 is likely to play an important role as a predictive biomarker for selecting patients deriving most benefit from anti-PD-1/PD-L1 monotherapy and directing patients with lower levels of tumor PD-L1 expression (with a high unmet medical need), to alternative treatments, such as combination immunotherapies.

Burden of diabetic foot disorders, guidelines for management and disparities in implementation in Europe: a systematic literature review.

The study aimed to assess the economic and quality of life burden of diabetic foot disorders and to identify disparities in the recommendations from guidelines and the current clinical practice across the EU5 (Spain, Italy, France, UK and Germany) countries. Literature search of electronic databases (MEDLINE®, Embase® and Cochrane Database of Systematic Reviews) was undertaken. English language studies investigating economic and resource burden, quality of life and management of diabetic foot disease in the EU5 countries were included. Additionally, websites were screened for guidelines and current management practices in diabetic foot complication in EU5. Diabetic foot complications accounted for a total annual cost of €509m in the UK and €430 per diabetic patient in Germany, during 2001. The cost of diabetic foot complications increased with disease severity, with hospitalizations (41%) and amputation (9%) incurring 50% of the cost. Medical devices (orthopaedic shoes, shoe lifts and walking aids) were the most frequently utilized resources. Patients with diabetic foot complications experienced worsened quality of life, especially in those undergoing amputations and with non-healed ulcers or recurrent ulcers. Although guidelines advocate the use of multidisciplinary foot care teams, the utilization of multidisciplinary foot care teams was suboptimal. We conclude that diabetic foot disorders demonstrated substantial economic burden and have detrimental effect on quality of life, with more impairment in physical domain. Implementation of the guidelines and set-up of multidisciplinary clinics for holistic management of the diabetic foot disorders varies across Europe and remains suboptimal. Hence, guidelines need to be reinforced to prevent diabetic foot complications and to achieve limb salvage if complications are unpreventable.

Efficacy and safety of BG-12 (dimethyl fumarate) and other disease-modifying therapies for the treatment of relapsing-remitting multiple sclerosis: a systematic review and mixed treatment comparison.

OBJECTIVE: Currently, direct comparative evidence or head-to-head data between BG-12 (dimethyl fumarate) and other disease-modifying treatments (DMTs) is limited. This study is a systematic review and data synthesis of published randomized clinical trials comparing the efficacy and safety of existing DMTs to BG-12 for relapsing-remitting multiple sclerosis (RRMS). METHODS: A systematic review was conducted by searching MEDLINE, EMBASE, and the Cochrane Library for English-language publications from 1 January 1960 to 15 November 2012. Clinicaltrials.gov, metaRegister of Controlled Trials, and conference proceedings from relevant annual symposia were also hand searched. Two independent reviewers collected and extracted data, with discrepancies reconciled by a third reviewer. Included studies were randomized controlled trials (RCTs) of DMTs (interferon [IFN] beta-1a, IFN beta-1b, glatiramer acetate [GA], BG-12, fingolimod, natalizumab, and teriflunomide) in adults with RRMS. Mixed treatment comparisons were conducted to derive the relative effect size for the included treatments. Annualized relapse rate (ARR), disability progression, and safety outcomes were assessed. RESULTS: BG-12 240 mg twice a day (BID) significantly reduces ARR compared to placebo (rate ratio: 0.529 [95% CI: 0.451-0.620]), IFNs (0.76 [95% CI: 0.639-0.904]), GA (0.795 [95% CI: 0.668-0.947]), and teriflunomide 7 mg and 14 mg (0.769 [95% CI: 0.610-0.970] and 0.775 [95% CI: 0.614-0.979]), and does not show a significant difference when compared to fingolimod. Only natalizumab was significantly superior to BG-12 in reducing ARR. BG-12 also demonstrated favorable results for disability and safety outcomes. CONCLUSION: Based on indirect comparison, BG-12 offers an effective oral treatment option for patients with RRMS with an overall promising efficacy and safety profile compared to currently approved DMTs. Key limitations of the systematic review were the large heterogeneity in patients enrolled and the variability in the definition of outcomes in included trials.

Efficacy and tolerability of naproxen/esomeprazole magnesium tablets compared with non-specific NSAIDs and COX-2 inhibitors: a systematic review and network analyses.

Non-steroidal anti-inflammatory drugs (NSAIDs), such as non-selective NSAIDs (nsNSAIDs) or selective cyclooxygenase-2 (COX-2) inhibitors, are commonly prescribed for arthritic pain relief in patients with osteoarthritis (OA), rheumatoid arthritis (RA), or ankylosing spondylitis (AS). Treatment guidelines for chronic NSAID therapy include the consideration for gastroprotection for those at risk of gastric ulcers (GUs) associated with the chronic NSAID therapy. The United States Food and Drug Administration has approved naproxen/esomeprazole magnesium tablets for the relief of signs and symptoms of OA, RA, and AS, and to decrease the risk of developing GUs in patients at risk of developing NSAID-associated GUs. The European Medical Association has approved this therapy for the symptomatic treatment of OA, RA, and AS in patients who are at risk of developing NSAID-associated GUs and/or duodenal ulcers, for whom treatment with lower doses of naproxen or other NSAIDs is not considered sufficient. Naproxen/esomeprazole magnesium tablets have been compared with naproxen and celecoxib for these indications in head-to-head trials. This systematic literature review and network meta-analyses of data from randomized controlled trials was performed to compare naproxen/esomeprazole magnesium tablets with a number of additional relevant comparators. For this study, an original review examined MEDLINE®, Embase®, and the Cochrane Controlled Trials Register from database start to April 14, 2009. Using the same methodology, a review update was conducted to December 21, 2009. The systematic review and network analyses showed naproxen/esomeprazole magnesium tablets have an improved upper gastrointestinal tolerability profile (dyspepsia and gastric or gastroduodenal ulcers) over several active comparators (naproxen, ibuprofen, diclofenac, ketoprofen, etoricoxib, and fixed-dose diclofenac sodium plus misoprostol), and are equally effective as all active comparators in treating arthritic symptoms in patients with OA, RA, and AS. Naproxen/esomeprazole magnesium tablets are therefore a valuable option for treating arthritic symptoms in eligible patients with OA, RA, and AS.